The Neuronal Adaptor Protein X11α Reduces Aβ Levels in the Brains of Alzheimer's APPswe Tg2576 Transgenic Mice

Increased production and deposition of the 40-42-amino acid β-amyloid peptide (Aβ) is believed to be central to the pathogenesis of Alzheimer's disease. Aβ is derived from the amyloid precursor protein (APP), but the mechanisms that regulate APP processing to produce Aβ are not fully understood. X11α (also known as munc-18-interacting protein-1 (Mintl)) is a neuronal adaptor protein that binds APP and modulates APP processing in transfected non-neuronal cells. To investigate the in vivo effect of X11α on Aβ production in the brain, we created transgenic mice that overexpress X11α and crossed these with transgenics harboring a familial Alzheimer's disease mutant APP that produces increased levels of Aβ (APPswe Tg2576 mice). Analyses of Aβ levels in the offspring generated from two separate X11α founder mice revealed a significant, approximate 20% decrease in Aβ(1-40) in double transgenic mice expressing APPswe/X11α compared with APPswe mice. At a key time point in Aβ plaque deposition (8 months old), the number of Aβ plaques was also deceased in APPswe/X11α mice. Thus, we report here the first demonstration that X11α inhibits Aβ production and deposition in vivo in the brain.